Phenyl alkyl amine derivatives to treat inflammation

ABSTRACT

PHENYL ALKYL AMINE DERIVATIVES IN WHICH THE PHENYL RING IS SUBSTITUTED BY A PIPERIDINO GROUP. THE COMPOUNDS POSSESS CENTRAL NERVOUS SYSTEM ACTIVITY AND A POWERFUL ANTIINFLAMMATORY ACTION.

United States Patent 3,830,923 PHENYL ALKYL AMINE DERIVATIVES T0 TREATINFLAMMATION William Robert Nigel Williamson, Farnham Common, TerenceAlan Hicks, Farnborough, and Elaine Hilda Day (nee Quinnell), Reading,England, assignors to Lilly Industries Limited, London, England NoDrawing. Continuation-impart of abandoned application, Ser. No. 316,966,dated Dec. 20, 1972, which was a divisional of Ser. No. 125,421, datedMar. 17,

1971, now US. Patent No. 3,729,475, which was a continuation-in-part ofabandoned application Ser. No. 866,026, dated Oct. 13, 1969. Thisapplication Aug. 27, 1973, Ser. No. 391,725

Int. Cl. A61k 27/00 US. Cl. 424-267 10 Claims ABSTRACT OF THE DISCLOSUREPhenyl alkyl amine derivatives in which the phenyl ring is substitutedby a piperidino group. The compounds possess central nervous systemactivity and a powerful antiinfiammatory action.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of our co pending application Ser. No. 316,966,filed Dec. 20, 1972, now abandoned, which was a division of our thencopending application Ser. No. 125,421, filed Mar. 17, 1971, now US.Pat. 3,729,475, which was in turn a continuation-in-part of our thenco-pending application Ser. No. 866,026, filed Oct. 13, 1969, nowabandoned.

SPECIFICATION The present invention provides novel phenyl alkyl aminederivatives of the formula:

EL [a] R LI LLL w r and pharmaceutically acceptable acid addition saltsthereof, wherein R and R are independently hydrogen or C alkyl; 11 is aninteger from 1 to 4; m is zero or 1; R is hydrogen or in no more thanone instance where it occurs is C alkyl; R and R are independently hy:drogen or C alkyl; R is metaor para-piperidino; and R is hydrogen,chloro, bromo or methyl.

Preferred compounds falling within the scope of compounds defined informula I above are those having one or more of the followingcharacteristics:

(a) R is hydrogen, methyl or ethyl and m is 1;

(b) R is hydrogen, methyl or ethyl and m is 1; p

(c) R is hydrogen or methyl, n is 0 or 1, and m is 1; (d) the group hasa total of from 2 to 6 carbon atoms; (e) R is hydrogen or methyl; (f) Ris hydrogen or methyl; (g) R is ortho to the group R The most preferredgroup of compounds of the present invention have the structure:

ice

and acid addition salts thereof, wherein R R and R are independentlyhydrogen or methyl, and R is hydrogen, chloro or bromo.

The present invention also provides a process for preparing thecompounds of formula I characterised in that a process known to beuseful in the synthesis of N-phenyl heterocyclic amines or phenyl alkylamines is used. Such known methods are well documented in the scientificliterature and are well known to chemists skilled in the art who mayreadily adapt the known processes to prepare the compounds of thisinvention. Thus, for example, the known process for preparing anN-phenyl piperidine comprising condensing a haloor amino-benzene withpiperidine or with a 1,5-dihalopentane respectively may be adapted toproduce a process for preparing the compounds of this inventioncomprising reacting a haloor amino-phenyl alkyl amine of the formula:

LU [5Q X III where Y is halo and Z is CH where a is 2, 3 or 4.

This reaction of a compound of formula III with the amine R H or acompound of formula IV may be carried out in a known manner, thereactants being reacted at or below room temperature or at elevatedtemperatures-depending on the nature of the particular reactants-in asuitable solvent such as alcohol, benzene, toluene, dimethylsulphoxide,chloroform, tetrahydrofuran or dimehylformamide. If a compound in whichR and R are both hydrogen is to be prepared by this method, then the NRR group may be protected, for example by acylation, during thecondensation and thereafter the protecting group removed, for example,by hydrolysis in the case of an acyl protecting group.

Similarly known methods for the preparation of phenyl alkyl amines maybe adapted in conventional manner to prepare the compounds of thisinvention. Such known methods generally involve the conversion of abenzene derivative having a substituent which is convertible byreduction, hydrolysis or the like to the required aminoalkylsubstituent. Accordingly these known processes may be modified toprovide a process for preparing the compounds of formula I characterisedin that a compound of the formula:

D R V substituent, is treated in such a manner as to produce the desiredconversion.

Most commonly group R is a substituent capable of being reduced to thedesired substituent. Exemplary of reducible substituents and theend-products of the reduction are:

L 1 r11 rul Lid. Li. if

where m, n, R R and R are as defined above, R represents R or hydroxyl,halogen, acetoxy, acetylthio, benzoyloxy or another group replaceable byhydrogen under the reduction conditions employed, and R represents CN orthe group R8 H-Na;

R R R R 1 a R iUiaLaN La 7 HQ U J L JH L I LL Jr. where R R R R R R, mand n are as defined above and R is oxygen or sulphur, provided that Rmay additionally be hydroxyl or benzoyloxy when R is hydrogen;

(iii) an sum R n NH:

where R R R R", m and n are as defined above, provided that at least oneof the R groups in the oxime starting material is hydrogen and providedthat, in addition to the definition given above, the other R group mayrepresent phenoxyalkyl, the phenoxy moiety of which is removed under thereaction conditions employed. The phenylsulphonyl or toluenesulphonylderivatives of the oxime may also be used, the corresponding acidaddition hi an,

salt of the amine being obtained;

(It should be noted that, in reaction (i) to (iii) above,

the group l "1 Ti i ht.-.

has been shown as a fully saturated group but it may, as is well knownin the art, contain at least one double bond which becomes saturatedduring the reduction.)

where R is --NO or NO when R is NO, R is chloro or bromo and R ishydrogen; and when R is NO;, R represents R and R is hydrogen, or Rtogether with R represent a valency bond;

HN lilo Q2; lEliiH L LL L ILLL R reducing agent such as sodium oraluminium amalgam in ethanol, zinc and hydrochloric acid, sodium inethanol, diborane, diethylsilane and boron trichloride, hydrazinehydrate in the presence of Raney nickel, Raney nickel in aqueous alkali,lithium aluminium hydride either alone or together with aluminiumchloride, or sodium borohydride optionally in the presence of palladium,copper, platinum or nickel salts or together with cobaltous chloride.

In addition to group R in formula V which may be reduced as above toproduce the desired compounds of formula I, other R groups may beconverted by various other methods to yield the desired compounds.Exemplary of such other reactions are:

where R R R in and n are as defined above and R is NCO, NHCO R (where Ris alkyl), CO'N or il NH,

The desired conversion of the isocyanate or urethan intermediate may becarried out by hydrolysis under alkaline conditions, for example usingpotassium or sodium hydroxide, or under acid conditions, for exampleusing concentrated hydrochloric acid. The isocyanate may be obtained bya number of methods including the Lassen reaction (treatment of thecorresponding hydroxamic acid-R" represents CO.NHOH- with a stronginorganic acid), the Hofmann degradation reaction (treatment of thecorresponding amide-R represents CO.NH with bromine, chlorine, or analkali metal hypobromite or hypochlorite, and an alkali such aspotassium hydroxide) and the Curtius reaction (treatment of thecorresponding acid azide-R" represents C0N --with benzene or chloroformat elevated temperatures). The urethan intermediate may be obained fromthe isocyanate by warming with an alcohol R OH, or by a modification ofthe Hofmann reaction using bromine and an alkali metal alkoxide, or by amodification of the Curtius reaction involving boiling the acid azide inthe alcohol R -OPI. When R is CON a further modification of the Curtiusreaction involving heating the acid azide with bromine in carbontetrachloride produces the desired amine directly. The phthalimidointermediate may be converted to the desired amine by hydrolysis underthe conditions given above or by treatment with hydrazine. Thephthalimido intermediate is obtained by using Gabriel's reactioninvolving reacting the corresponding compound where R is halogen withpotassiophthalimide. It will of course be appreciated that theintermediate shown in the above reaction sequence (vi) need not beisolated prior to conversion to the amine and the final reaction stepmay readily, and will commonly, be carried out in the reaction medium inwhich the interl OOOH or CE NH.CHO.

When the aldehyde or acid intermediate is used, the conversion may beaccomplished using the Schmidt reaction, ie by treatment with hydrazoicacid or its sodium or potassium salts in the presence of concentratedsulphuric acid. In the case of the aldehyde intermediate, :1 mixture ofthe corresponding nitrile and formamide is obtained. The mixture may bereduced, for example using hydrogen over Raney nickel, to produce thedesired amine. The formamide may also be converted to the amine byhydrolysis using for examples sodium hydroxide or sulphuric acid. Theformamide may be prepared from the aldehyde or a ketone in which R is R3R5 .'..J a.-.

L Jn-l using the Leuckart reaction involving treatment of the aldehydeor ketone with excess ammonium formateor formamide itself. As withreaction (vi) above, the intermediates need not be isolated from themedium in which they are prepared prior to their conversion to theamine.

(VIII) I L J. b LL J.

wherein R R R m and n are as defined above and Hal. is a halogen atom,the conversion being achieved either by reaction withhexamethylenetetramine in hot ethanol and in the presence of sodiumiodide, or by formation of a Grignard reagent followed by reaction withchloramine or, when Hal. is chloro or bromo, with O-methylhydroxylamine.The halogeno intermediate may also be reacted with the amine HNR R atleast one of R and R being other than hydrogen, and, if desired, aresultant amide (R is an acyl group) may be hydrolysed with for exampleconcentrated hydrochloric acid to yield the amine.

Elam. i

Ll: 1.6003; Lin

where R R R and m are as defined above, the decarboxylation beingaccomplished by heating, optionally in the presence of barium hydroxide.If desired, the amino group may be protected during the reaction, forexample by prior reaction with acetophenone or benzophenone, and thefree amine liberated, after decarboxylation, by acid hydrolysis.

CH-NH:

where R and R are as defined above, the conversion being carried out byhydroboration of the styrene intermediate using diborane, followed bytreatment with chloramine or hydroxyamino-O-sulphonic acid.

(xi) When R in formula V is hydrogen, by reaction with a cyclic imine offormula:

in the presence of a Friedel-Crafts catalyst such as aluminium chloride,to produce the desired compound of formula I in which m and n are both1.

It will be appreciated that the substitutents R R and R in the desiredcompound of formula I may be converted to another substitutent fallingwithin the definition of these groups in formula 1. Such a conversionmay be carried out at an intermediate stage of the above reactionsequences or as the ultimate step. An amino group R prepared from anitro group by reduction, may be replaced by halogen using the wellknown Sandmeyer or Gattermann reactions. The amino group NR R (at least6 one of R or R being hydrogen) may readily be alkylated or acylated byconventional procedures to produce the corresponding alkylamino oracylamino compounds.

The novel compounds of formula I may be isolated from the process of thepresent invention either as the free base or in acid addition salt form.The latter is, for most purposes of the present invention, the preferredform and includes particularly the pharmaceutically acceptable non-toxicaddition salts with suitable acids, such as those with inorganic acidsor acid salts such as sodium hydrogen carbonate, hydrochloric acid,hydrobromic acid, nitric acid, sulphuric acid or phosphoric acid, orwith organic acids, such as organic carboxylic acids, for examplesuccinic, glycol'lic, maleic, hydroxymaleic, malic, tartaric, citric,salicylic, o-acetyloxybenzoic, nicotinic or ison-icotinic acid, ororganic sulphonic acids, for example methane sulphonic, ethanesulphonic, Z-hydroxyethane sulphonic, toluene-p-sulphonic ornaphthalene-2-sulphonic acid.

A resulting acid addition salt may be converted into the free compoundaccording to known methods, for example, by treating it with a base,such as with a metal hydroxide or alkoxide, for example, an alkali metalor alkaline earth metal hydroxide, for example, lithium hydroxide,sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metalcarbonate, such as an alkali metal or an alkaline earth metal carbonateor hydrogen carbonate, for example sodium, potassium or calciumcarbonate or hydrogen carbonate; with ammonia; or with a hydroxylion-exchange preparation, or with any other suitable reagent.

A resulting acid addition salt may also be converted into another acidaddition salt according to known methods; for example, a salt with aninorganic acid may be treated with a metal salt, for example a sodium,barium or silver salt, of an acid in a suitable diluent, in which aresulting inorganic salt is insoluble and is thus removed from thereaction medium. An acid addition salt may also be converted intoanother acid addition salt by treatment with an anion exchangepreparation.

If the compounds of formula I contain an asymmetry centre, they areusually obtained in racemic form. If they have two or more asymmetrycentres, then these compounds are generally obtained in the form ofmixtures of racemates; the individual racemates can be isolated andobtained in pureform from these mixtures in known manner, for example byrepeated recrystallization from suitable solvents. These racemates canbe separated into their optical antipodes by a number of known methodsas indicated in the literature.

Thus, some racemic mixtures can be precipitated in the form of eutecticsinstead of in theform of mixed crystals and can be separated quickly inthis way; in these cases, selective precipitation may also be possible.The method of chemical separation is, however, generally preferable. Forthis purpose, diastereomers are formed from the racemic mixture byreaction with an opticallyactive separating agent. Thus the compounds offormula I may be converted to salts by reaction with optically activeacids, such as D- and L-tartaric acid, dibenzoyl 'D- and L-tartaricacid, diacetyl D- and L-tartaric acid, fi-camphosulphonic acid, D- andL-mandelic acid, D- and L-ma'lic acid or 'D- and L-lactic acid. Thedifference in the solubility of the diastereomers obtained permitsselective crystallisation of one form and regeneration of the opticallyactive amine of formula I from the mixture. In addition, opticallyactive compounds can, of course, be obtained by the above mentionedprocesses by using start-'- ing materials whch are already opticallyactive.

As stated above, the compounds of formula I have been found to possessvaluable pharmacological properties in that they have been found toaffect the central nervous system of animals when administered at dosesof from 1 to 250 mg./kg. In particular, their C.N.S.

action is such as to render the compounds useful as anorexic,anti-hallucinogenic and anti-Parkinson agents. In addition, thecompounds possess a powerful antiinflammatory action at the abovementioned doses without detectable incidence of gastric irritation whichis a common defect of most known acidic anti-inflammatory agents. Inhumans, doses of from about 1 to 25 mg./kg. will normally produce therequired pharmacological effect although it will be appreciated that thehuman dosage regime will be determined by a physician in the light ofall the relevant circumstances including the condition to be treated,the physical condition of the patient, the choice of compound to beadministered and the route of administr-ation and therefore the abovedosage range is not intended to limit the scope of the invention in anyway.

The compounds of formula I will normally be administered in compositionform and accordingly the present invention also provides pharmaceuticalcompositions comprising at least one compound of formula I inassociation with a pharmaceutically acceptable carrier therefor.

The compositions of the present invention may be administered orally,parenterally or rectally in the form of, for example, tablets, capsules,suppositories or suspensions. Advantageously for this purpose,compositions may be provided in dosage unit form preferably each dosageunit containing from to 1000 mg., more advantageously 50 to 750 mg., ofa compound of formula I.

In this spectification the expression dosage unit form is used asmeaning a physically discrete unit containing an individual quantity ofthe active ingredient, generally in admixture with a pharmaceuticaldiluent therefor or otherwise in association with a pharmaceuticalcarrier, the quantity of the active ingredient being such that one ormore units are normally required for a single therapeutic administrationor that, in the case of sever-able units such as scored tablets, atleast one fraction such as a half or quater of a severable unit isrequired for a single therapeutic administration.

The formulation of the present invention normally will consist of atleast one compound of formula I mixed with a carrier, or diluted by acarrier, or enclosed or encapsulated by a carrier in the form of acapsule, sachet, cachet, paper or other container. A carrier or diluentmay be a solid, semi-solid or liquid material which serves as a vehicle,excipient or medium for the active therapeutic substance. Some examplesof the diluents or carriers which may be employed in the pharmaceuticalformulations of the present invention are lactose, dextrose, sucrose,sorbitol, mannitol, starch, gum acacia, calcium phosphate, liquidparaffin, cocoa butter, oil of theobroma, alginates, tragacanth,gelatin, syrup -B.P., methyl cellulose, polyoxyethylene sorbitanmonolaurate, and methyland propyl-hydroxybenzoate. In the case oftablets, a lubricant may be incorporated to prevent sticking and bindingof the powdered ingredients in the dies and on the punch of thetabletting machine. For such purpose, there may be employed for instancetalc, aluminium, magnesium or calcium stearate or mineral oil.

The following examples will further illustrate the preparation of thenovel compounds of this invention:

EXAMPLE 1 4-Piperidinophenylacetonitrile (5 g., 0.025 mole) in 12%ammonia in ethanol (50 ml.) was hydrogenated over Raney nickel catalyst(2.5 g.) at 60 p.s.i. to give 4-piperidinophenylethylamine, b.p. 1l7-120C./0.15 mm. Hg which was converted to its dihydrochloride by treatmentwith hydrogen chloride in ether, m.p. 233-235 C. after recrystallisationfrom ethanol, To the dihydrochloride in water was added sodium hydrogencarbonate. After standing for 1 /2 hours, filtering, washing and drying,the carbonate was obtained, m.p. 91-95 C. The ethylamine was alsoobtained by reduction of the nitrile using lithium aluminium hydride.

Similarly 3-piperidinophenylethylamine, b.p. 1101l2 C./ 0.15 mm. Hg andits dihydrochloride, m.p. 218220 C., were prepared from3-piperidinophenylacetonitrile; 2- (4-piperidinophenyl) propylamine,b.p. ll2-ll4 C./0.25 mm. Hg, its dihydrochloride, m.p. 226229 C., andits hemi-carbonate, hemi-hydrate, m.p. 79-82 C. (dec.), were preparedfrom 2(4-piperidinophenyl)propionitrile;2-(3-piperidinophenyl)propylamine, b.p. 122-124 C./0.3 mm. Hg and itssuccinic acid salt, m.p. 141-142 C. were prepared from2-(3-piperidinophenyl)propionitrile; 2-(3- m.p. 216225 C., was preparedfrom 2-(3-chloro-4-piperidinophenyl)propionitrile; 3-chloro 4Piperidinophenylethylamine, b.p. 163l64 C./3 mm. Hg and itsdihydrochloride, m.p. 198-200 C. were prepared from 3-chloro-4-piperidinophenylacetonitrile; 3-(4 piperidinophenyl)propylaminedihydrochloride, m.p. 180 C. (dec.) was prepared from3-(4-piperidinophenyl)propionitrile; and2,2-dimethyl-2-(4-piperidinophenyl)ethyl amine and its succinic acidsalt, m.p. 15516l C., were prepared from 2,2-dimethyl-2-4-piperidinophenyl acetonitrile.

EXAMPLE 2 (a) 4 Piperidinophenylethylamine (9.5 g., 0.0465 mole) wasrefluxed for 8 hours with formic acid (11.9 g., 0.23 mole) and 40%(w./v.) formaldehyde solution (7.7 ml., 0.1 mole). Concentratedhydrochloric acid (4.2 ml., 0.05 mole) was added and the mixtureevaporated to dryness at 50 C. in vacuo. The residue was dissolved inwater, made basic with 25% sodium hydroxide and extracted with ether.The ethereal extract was Washed with saturated sodium chloride solution,dried (K CO and filtered. The ether was evaporated to give N,N'dimethyl-4-piperidinophenylethylamine, b.p. 121- 123 C./ 0.02 mm. Hg,which, on treatment with ethereal hydrogen chloride, yieldedN,N-dimethyl-4-piperidinophenylethylamine dihydrochloride, m.p. 250253C. from absolute ethanol. Similarly,N,N-dimethyl-2-(4-piperidinophenyl)propylamine dihydrochloride, m.p.240- 243 C., was obtained.

(b) 4 Piperidinophenylethylamine dihydrochloride (27.7 g.) was stirredat room temperature for 20 hours in trifluoroacetic anhydride (50 ml.).The solution was poured into saturated sodium hydrogen carbonatesolution (750 ml.), the precipitated solid filtered off, washed withwater and dried at room temperature, under vacuum, to giveN-trifluoroacetyl 4 iperidinophenylethylamine, m.p. -112" C. Similarlyusing 2-(4-piperidinophenyl)propylamine dihydrochloride and aceticanhydride or trifiuoroacetic anhydride, there was obtained N-acetyl-2-(4-piperidinophenyl)propylamine, m.p. 7073 C. and N-trifluoroacetyl 2(4-piperidinophenyl)propylamine, m.p. 84-87 C., respectively.

(c) N-Trifiuoroacetyl-4-piperidinophenylethylamine (3 g.) in dry acetone(50 ml.) with methyl iodide (5.7 g.) was warmed nearly to reflux andpowdered potassium hydroxide (2.24 g.) was added. The mixture was heatedunder reflux for 5 minutes, excess methyl iodide and acetone wereremoved on a rotary evaporator and water (50 ml.) was added and themixture extracted with ether. The combined ethereal extracts containingN-methyl-N- trifluoroacetyl-4-piperidinophenylethylamine were evaporatedand the residue refluxed for 3.5 hours in 90% ethanol containingpotassium hydroxide (17.50 g.). The solution was diluted with water,extracted with ether, the ether extracts washed with saturated sodiumchloride solution, dried (Na SO and filtered and evaporated to give anoil. This was dissolved in boiling ethanol and added to a solution ofsuccinic acid in ethanol to give the succinic acid salt ofN-methyl-4-piperidinophenylethylamine, m.p. 132133 C. SimilarlyN-methyl-Z-(4-piperidinophenyl)propylamine dihydrochloride, m.p. 240245C was obtained.

Using similar procedures to those described in Examples (a) to (c)above, the following derivatives of the primary amines prepared inExample 1 can be obtained:

N,N-dimethyl-3-piperidinophenylethylamine dihydrochlorideN-methyl-N-ethyl-Z- (4-piperidinophenyl propylarnine dihydrochlorideN,N-diethyl-2- (4-piperidinophenyl propylamineN-methyl-Z-(4-piperidinophenyl)propylamine, succinic acid saltN,2,2-trimethyl-2-( 4-piperidinophenyl ethylamine dihydrochloride.

' EXAMPLE 3 A solution of 2-(4-piperidinophenyl)propionamide (3.65 g.,0.016 mole) in boiling dry benzene (60 ml.) was added during 5 minutesto a stirred suspension of lithium aluminium hydride (1.8 g., 0.048mole) in dry ether (35 ml.), refluxed for 1 hour and then stir-red atroom temperature for 1 hour. The mixture was cooled and cautiouslydecomposed by dropwise addition of water (1.8 ml.), followed by 15%sodium hydroxide solution (13 ml.) and finally water (5.4 ml.). Themixture was stirred for /2 hour, filtered and the residue washed withether. The ethereal filtrate and washings were combined, and dried overmagnesium sulphate. The ether was concentrated and the residue distilledto give 2-(4- piperidinophenyl)-propylamine, b.p. 112114 'C./0.25 mm.Hg, which was then converted to its dihydrochloride, m.p. 226229 C.

Using a similarreduction procedure, the following compounds wereprepared: 4-piperidinophenylethylamine, b.p. 1l7120 C./0.15 mm. Hg, andits dihydrochloride, m.p. 233235 C., by reduction of4-piperidinophenylacetamide; 4-(4-piperidinophenyl)butylamine and itssuccinic acid salt, m.p. 158-160 C., by reduction of4-(4-piperidinophenyl)butyramide; 2-(3 piperidinophenyl)propylamine,b.p. 122l24 C./0.3 mm. Hg, by reduction of 2-(3piperidinophenyl)propionamide; N,N dimethyl-4-piperidinophenylethylamine dihydrochloride, m.p. 250- 253 C., byreduction of N,N-dimethyl-4-piperidinophenylacetamide;N,2,2-trimethyl-2-(4-piperidinophenyl)ethylamine dihydrochloride byreduction of N,2,2-trimethyl-2- (4-piperidinophenyl acetamide; 4-(3-chloro-4-piperidinophenyl)butylamine and its succinic acid salt, m.p.147- 149 C., by reduction of 4-(3-chloro-4-piperidinophenyl) butyramide;3-chloro-4-piperidinophenylethylamine by reduction of3-chloro-4-piperidinophenylacetamide; 3-(4- piperidinophenyl)propylaminedihydrochloride, m.p. 180 C. (dec.) by reduction of3-(4-piperidinophenyl)propionamide; and 2,2-dimethyl 2(4fipiperidinophenyl) ethyl amine succinic acid salt, m.p. 155161 C., byreductionof 2,2-dimethyl-2-(4-piperidinophenyl)acetamide.

EXAMPLE 4 (a) fi-Nitro-3-chloro-4-piperidinostyrene (5.15 -g.)preparable by the known method of reacting the correspondingbenzaldehyde in glacial acetic acid containing ammonium acetate withnitromethanein ether (70 ml.) was added dropwise to lithium aluminiumhydride (2.6 g., 0.0688 mole) in ether (100 ml.) under nitrogen at sucha rate that gentle reflux was maintained (25 minutes) and stirred atroom temperature overnight. The mixture was cooled to C. and treatedwith water (5 ml.) followed by 20% sodium acetate trihydrate solution(150 1111.). The ether phase was separated and the aqueous phase was 3times extracted with ether. The ether was washed with sodium chloridesolution, dried (Na SO and evaporated to leave an oil which wasdistilled to give 3-c-hloro-4- piperidinophenylethylamine, b.p. 163-164C./ 3 mm. Hg. This was converted to its dihydrochloride by means ofhydrogen chloride in ether. The dihydrochloride formed flakey needles,m.p. 198-200 C. (dec.), from ethyl acetate-ethanol mixture.

(b) B-Methyl-B-nifiro-4piperidinostyrene (20.5 g.)-- obtainable bycondensation of 4-piperidinobenzaldehyde and nitroethanewas reduced asdescribed in Example (a) above to yieldl-methyl-Z-(4-piperidinophenyl)ethylamine, b.p. 116-120" C./ 0.15 mm.Hg, which was then converted to its succinic acid salt, m.p. 172173 C.By similar reductions of the corresponding nitrostyrenes, the followingcompounds were prepared: 3-piperidinophenylethylamine, b.p. -112 C./0.15mm. Hg, from B-nitro 3 piperidinostyrene;2-(4-piperidinophenyl)propylamine, b.p. 112114 C./ 0.25 mm. Hg, froma-methyl-B- nitro-4-piperidinostyrene;3-chloro-4-piperidinophenylethylamine, b.p. 163-1 64 C./3 mm. Hg, fromB-nitro-3- chloro 4 piperidinostyrene; and 1-ethyl-2-(3-methy1-4-piperidinophenyl)propylamine fromm-methyl-B-ethyl-finitro-3-methyl-4-piperidinostyrene. The primaryamines produced by this process are converted to secondary and tertiaryamines by the process of Example 2. v

EXAMPLE 5 2-(4-Fluorophenyl)propylamine (0.2 mole) and piperidine (0.24mole) were stirred for 3 hours at 100 C. in dimethyl sulphoxide (80 ml.)containing anhydrous potassium carbonate (0.2 mole). The reactionmixture was cooled, poured into water, extracted with ether, dried oversodium sulphate, filtered, evaporated and distilled to give2-(4-piperidinophenyl)propylamine, b.p. 112-114 C./0.25 mm. Hg.

By the use of similar condensation reactions, the following compoundswere prepared: 4-piperidinophenylethylamine, b.p. 117-120" C./0.15 mm.Hg, by condensing 4-chlorophenylethylamine and piperidine;2-(3-methyl-4- piperidinophenyl)propylamine by condensing2-(3-rnethyl-4-fiuorophenyl)propylamine and piperidine; 2,2-dimethyl-2-(4-piperidinophenyl)ethylamine succinic acid salt, m.p. 155161 C., andN,N,2,2-tetramethyl-2-(4apiperidinophenyl)ethylamine by condensingrespectively 2,2- dimethyl-2-(4-fiuorophenyl)ethylamine andN,N,2,2-tetramethyl-Z-(4 chlorophenyl)ethylamine with piperidine.

EXAMPLE 6 (a) N-Methyl 4 aminophenylethylamine (1 mole), potassiumcarbonate (1.1 mole), cuprous iodide (0.015 mole), potassium iodide(0.015mole) and 1,5-dibromopentane (1.5 mole) were stirred at C. for 5hours in dimethylformamide (200 ml.). After working up the r actionmixture as described in Example 2, N-methyl-4-piperidinophenylethylamine was obtained and isolated as its succinicacid salt, m.p. 132-133 C. Y

(b) N-Acetyl-2-(4-aminophenyl)propylamine 'was condensed with1,5-dibromopentane in the manner described at (a) above to yieldN-acetyl-2-(4-piperidinophenyl) propylamine. On hydrolysis withhydrochloric acid, 2-(4- piperidinophenyl)propylamine dihydrochloride,m.p. 226- 229 C., was obtained.

Using similar procedures to those described above, the followingcompounds were prepared: 4-piperidinophenylethylamine, b.p. 117120C./0.15 mm. Hg, by condensing N-acetyl-4-aminophenylethyla-mine with1,5-dich1oropentane followed by hydrolysis; 3-chloro 4piperidinophenylethylamine, b.p. 163164 C./ 3 mm. Hg, by condensingN-acetyl-3-chloro-4-aminophenylethylamine with 1,5-dichloropentanefollowed by hydrolysis; and1,2,2-trimethyl-2-(4-piperidinophenyl)ethylamine by condensing N-acetyl1,2,2 trimethyl-2-(4-aminophenyl)ethylamine with 1,5-dibrornopentanefollowed by hydrolysis.

EXAMPLE 7 The oxime (9.4 g.) of 2-(4-piperidinophenyl)propional dehydewas dissolved in ethanol and heated with stirring whilst 500 g. of 2'/z% sodium amalgam was added. The reaction mixture was kept acid bycontinual addition of acetic acid. At the completion of the reaction,the yellow liquid was freed of alcohol by steam distillation and theresidue warmed with water. The mixture was filtered to remove unchangedoxime and the filtrate yieldeda brown oil on addition of potassiumhydroxide solution. The mixture was extracted with ether and, afterremoval of the ether, the residue was distilled to give 7 g. of 2-(4-piperidinophenyl)propylamine, b.p. 112-114 C./ 0.25 mm. Hg.

Similarly by reduction of the oximes of other appropriate aldehydes thefollowing compounds can be prepared:

4-piperidinophenylethylamine dihydrochloride, m.p. 233-3-piperidinophenylethylamine, b.p. 110-112C./ 0.15 mm.

2-(3-piperidinophenyl)propylamine, b.p. 122-124 C./0.3

mm. Hg

2 (3 chloro-4-piperidinophenyl)propylamine dihydrochloride, m.p. 216-225C.

3-chloro-4-piperidinophenylethylamine, b.p. 163-164 C./

3 mm. Hg

3-methyl-4-piperidinophenylethylamine dihydrochloride2-(3-methy1-4-piperidinophenyl)propylamine3-(4-piperidinophenyl)propylamine dihydrochloride, m.p.

1 methyl 2-(4-piperidinophenyl)ethylamine, b.p. 116- 120 C./0.15 mm. Hg

2,2 dimethyl-2-(4-piperidinophenyl)ethylamine succinic acid salt, m.p.155-161 C.

The following secondary and tertiary amines can be prepared from theabove primary amines by the method of Example 2:

N,N dimethyl 4-piperidinophenylethylamine, b.p. 121- 123 C./0.02 mm. Hg

N,N dimethyl 2-(4-piperidinophenyl)propylamiue dihydrochloride, m.p.240-243 C.

N,N diethyl-Z-(4-piperidinophenyl)propylamine dihydrochlorideN-methyl-3- 4-piperidinophenyl propylamineN-ethyl-2-(3-chloro-4-piperidinophenyl)propylamine N-methyl-Z-(4-piperidinophenyl) propylamine N-methyl-4-piperidinophenylethylamine,m.p. 132-133 C.

EXAMPLE 8 2-(4-Piperidinophenyl-propionaldehyde (3 moles) was added to asolution of ammonia (51 g., 3 moles) in 300 ml. of cooled ethanol in anautoclave with g. of Raney nickel catalyst. Under an initial pressure of90 atmospheres, hydrogen absorption began at 40 C. and was complete inminutes at a final temperature of 70 C. Distillation of the filteredreaction product gave 251 g. of 2-(4-piperidinophenyl)propylamine, b.p.112-114 C./ 0.25 mm. Hg.

Using similar reaction conditions, the appropriate aldehyde, and ammoniaor the appropriate N-alkyl or N,N- dialkyl amine, the primary amines andthe N-alkyl and N,N-dialkylamines exemplified in Example 7 can beprepared. The resultant primary amines can also be converted tosecondary and tertiary amines by the method of Example 2.

EXAMPLE 9 (a) Ethyl 3-(4-piperidinophenyl)butyrate (0.1 mole), 85%hydrazine hydrate (7.5 ml., 0.1 mole) and absolute ethanol (10 ml.) wererefluxed for 6 hours. The hydrazide which crystallised from the cooledmixture was collected and washed with a little ether. The hydrazide Wasdissolved in 150 ml. of ice-water containing 17 ml. of 6N hydrochloricacid and to the solution was added with stirring a solution of sodiumnitrite (7.5 g.) in 20 ml. of water, the temperature being kept below 10C. At the end of the addition the mixture was stirred for a further 5minutes, made alkaline by the addition of solid sodium bicarbonate andextracted with 4X 50 ml. of ether. The ether was dried for 5 minutesover CaCl decanted into a flask containing ml. of absolute ethanol andthe ether distilled until the residual volume was ml. This solutioncontaining 3-(4-piperidinophenyl)butyric acid azide was boiled and theethanol distilled oil to leave N-[2-(4- piperidinophenyl)propyl]urethan,which was refluxed with 20 ml. concentrated hydrochloric acid and 10 ml.glacial acetic acid for 24 hours. The mixture was evaporated to dryness,treated with 2N sodium hydroxide solution, extracted with ether, theether dried and evporated off, and the residue distilled to give 6 g. of2-(4-piperidinophenyl) proplyamine, b.p. 112-114 C./0.25 mm. Hg. Thesame amine was obtained by heating the above acid azide with bromine incarbon tetrachloride or by heating the azide in benzene solution andhydrolysing the resultant isocyanate with boiling potassium hydroxide.

(b) 3 (4 Piperidinophenyl)butyric acid (40 g.) was stirred, withcooling, with bromine (54 g., 18 ml.) and a solution of potassiumhydroxide (20 g.) in water (200 ml.) was added. The resultant solutioncontaining 2-(4-piperidinophenyl)propyl isocynate was added to a stirredsolution of potassium hydroxide (56 g.) in water ml.) and thetemperature maintained at 60-70 C. until the yellow colour disappeared.The cooled solution was extracted with ether and, after the usualprocessing steps, the residue was distilled to yield 20 g. of2-(4-piperidinophenyl)propylamine, b.p. 112-114 C./0.25 mm. Hg.

Using similar reaction conditions to those described in (a) and (b)above and using the appropriate acid azide, urethan or isocyanate, theother primary amines exemplified in Example 7 can be prepared andconverted to secondary and tertiary amines by the process of Example 2.

EXAMPLE 10 (a) 3-(4-Piperidinophenyl)butyric acid (0.53 mole) inchloroform (500 ml.) was treated with concentrated sulphuric acid (30ml.) and the mixture stirred vigorously at 40 C. Hydrazoic acid (52 ml.of a 5.3% solution in chloroform; 1.2 mole) was added slowly and, afterevolution of nitrogen had ceased (2 hours), the mixture was poured intoexcess of sodium hydrogen carbonate solution. The chloroform layer wasseparated and the aqueous phase extracted with chloroform. The combinedchloroform extracts were dried (Na SO evaporated and the residuedistilled to give 2-(4-piperidinophenyl)propylamine, b.p. 112-114C./0.25 mm. Hg.

(b) 28% Ammonia (1.72 moles) and 90% formic acid 1.72 moles) werecautiously mixed, the temperature of the solution raised to 160 C., and0.344 mole of 4-piperidinophenylacetone added. The temperature wasmaintained at 160-170 C. for 7 hours. The resultant N-[lmethyl-2-(4piperidinophenyl)ethyl]formamide was hydrolysed by refluxing the mixturefor 8 hours with concentrated hydrochloric acid ml.). The mixture wastreated with charcoal, filtered, the filtrate made alkaline with ammoniaand the product extracted with ether. After evaporation of the ether,the residue was distilled to give l-methyl 2(4-piperidinophenyl)ethylamine, b.p. 126- 129 C. /0.2 mm. Hg.

By treating the appropriate acid or formamide in the manner described in(a) and (b) above, the other primary amines exemplified in Example 7 canbe prepared and can then be converted to secondary and tertiary aminesby the process of Example 2.

EXAMPLE 11 (a) A solution of O-methylhydroxylamine (141 g., 3 moles) inanhydrous ether (300 ml.) was added gradually with vigorous stirring toa solution of 2-(4-piperidinophenyl)propyl magnesium bromide (preparedfrom 6 moles of 2-(4-piperidinophenyl)propyl bromide) in ether (3litre), the temperature being maintained at -10 to 15 C. during theaddition. After addition was complete, the temperature was kept at --10C. for a further 30 minutes and then allowed to rise slowly to roomtemperature. Finally the reaction mixture was refluxed for 2 hours. Itwas then cooled and treated at 0 C. with 5N- hydrochloric acid (3litres), the layers being separated and the aqueous solution evaporatedto small bulk under reduced pressure. The residue was strongly basifiedwith 50% aqueous potassium hydroxide and extracted with ether. After theusual processing, distillation yielded 2-(4-piperidinophenyl)propylamine, b.p. 112-114 C./ 0.25 mm. Hg.

(b) A mixture of 2 (4-piperidiuophenyl)propyl bromide (0.4 mole) andanhydrous acetamide (94.4 g., 1.6 mole) was heated for 2 to 3 hoursunder reflux in an oil bath at 200 C. The mixture was cooled, treatedwith sodium hydroxide, extracted with ether, the extracts dried and theether removed to yield N-acetyl-2-(4-piperidinophenyl)propylamine (0.32mole), m.p. 70-73 C.

The amide was refluxed for Shows with concentrated hydrochloric acid(150 1111.), the solution evaporated to dryness and the base liberatedwith 40% potassium hydroxide. It was extracted with ether and, after theusual processing, distillation yielded 2-(4-piperidinophenyl)-propylamine, b.p. l12114 C./0.25 mm. Hg. The latter amine was alsoobtained by reaction of the above propyl bromide withhexamethylenetetramine in hot ethanol in the presence of sodium iodide.

Using the methods described at (a) and (b) above, the other primaryamines and N-acylated amines described in Example 7 can be prepared andcan then be converted to secondary and tertiary amines by the process ofExample 2.

EXAMPLE 12 A mixture of 2 amino-3-(4-piperidinophenyl)butyric acid (10g.) and acetophenone (40 g.) was heated for 2 hours at 150 C. undernitrogen. The mixture was cooled, treated with 3N-hydrochloric acid andthe aqueous layer separated. The organic layer was washed with water andthe aqueous layer and washings concentrated to yield (85%)2-(4-piperidinophenyl)propylamine dihydrochloride, m.p. 226229 C.

By using the above procedure applied to other suitable a-minoacids, theprimary amines described in Example 7 may be prepared and converted tosecondary and tertiary amines as described in Example 2.

EXAMPLE 13 a-Methyl-4-piperidinostyrene (5.03 g.) in tetrahydrofuran (4ml.) was flushed with nitrogen and 8.3 ml. of a 1M solution of diboranein tetrahydrofuran was added. The mixture was stirred at roomtemperature for 1 hour and then treated with sodiumhydroxylamine-O-sulphonic acid (2.08 g.). The mixture was refluxed for 3hours, cooled and acidified with ZN-hydrochloric acid. Treatment withsodium hydrogen carbonate (8 g.) gave an oil which was extracted withether. After the usual processing, the oil was distilled to yield 2(4-piperidinophenyl)propylamine, b.p. 112114 C./0.25 mm. Hg.

Using appropriately substituted styrenes, the following amines wereprepared by the above procedure:

4piperidinophenylethylamine dihydrochloride, mp.

3-piperidinopheny1ethylamine, b.p. 110-112 C./0.15

mm. Hg

2-(3-piperidinophenyl)propylamine, b.p. 122-124 C./0.3

mm. Hg

2- 3-chloro-4-piperidinopheny1) propylamine dihydrochloride, mp. 216-225C.

3 chloro 4 piperidinophenylethylamine, b.p. 163164 C./ 3 mm. Hg

3 methyl-4-piperidinophenylethylamine dihydrochloride 2-3-methyl-4-piperidinophenyl propylamine 1methyl-2-(4-piperidinophenyl)ethylamine, b.p. 116-120 C./0.l5 mm. Hg.The following secondary and tertiary amines can be prepared from theabove primary amines by the method of Example 2:

N,N dimethyl 4-piperidinophenylethylamine, b.p. 121- 123 C./0.02 mm. Hg

14 N,N dimethyl-Z-(4-piperidinophenyl)propylamine dihydrochloride, mp.240243 C. N,N-diethyl-2-(4-piperidinophenyl)propylamine dihydrochlorideN-methyl- 2- (3 -methyl-4-pip eridinophenyl propylamin N-methyl-2-(4-piperidinophenyl propylamine N-methyl-4-piperidinophenylethylamine,m.p. 132133 C.

EXAMPLE 14 To dry N-phenylpiperidine (14 ml.) and powdered aluminumchloride'(l0.2 g.) was added with stirring at below 15 C. a 0.04Msolution of 1,2-propyleneimine. After stirring at room temperature for30 minutes, the mixture was chilled, then sealed in an ampoule and keptfor 7 to 8 hours at -180 C. It was then poured into an ice-cold solutionof potassium hydroxide in water, the liberated oil extracted with ether,and after the'usual pr ocessing, the product was fractionally distilledto give 1- methyl-Z- (4-piperidinophenyl) ethyl'amine, b.p. 126-129C./0.2 mm. Hg and 2-(4-piperidinophenyl)propylamine, b.p. 112-114C./0.25 mm. Hg in the ratio of 1:4.

Using similar procedures, the following amines can be prepared:

2-(3-chloro-4-piperidinophenyl)propylamine dihydrochloride, mp. 216-225C. 2-(3-methy1-4-piperidinopheny1)propylamine.

The following secondary and tertiary amines can be prepared from theabove primary amines by the method of Example 2:

N,N dimethyl-Z-(4-piperidinophenyl)propylamine dihydrochloride, m.p.240243 C.

N,N-diethyl-Z-(4-piperidinophenyl)propylamine dihydrochlorideN-methyl-2- 3-methyl-4-piperidinophenyl propylamineN-methyl-2-(4-piperidinophenyl)propylamine.

We claim:

1. A method of treating inflammatory conditions in mammals whichcomprises administering to a mammal suffering from an inflammatorycondition 1 to 250 mg./kg. of mammalian body weight per day of acompound of the formula:

itltild Ra L I J L J.

or a pharmaceutically acceptable acid addition salt thereof, wherein R Rand R are independently hydrogen or methyl, and R is hydrogen, chloro orbromo.

3. A method as defined in Claim 2, wherein the compound which isadministered is 4-piperidino-j3-methylphenylethylamine or apharmaceutically acceptable salt thereof.

4. A method as defined in Claim 2, wherein the compound which isadministered is 4-piperidinophenylethylamine or a pharmaceuticallyacceptable acid addition salt thereof.

5. A method as defined in Claim 2, wherein the compound which isadministered is 2-(4-piperidinophenyl) propylamine or a pharmaceuticallyacceptable acid addition salt thereof.

6. A method as defined in Claim 1, wherein the compound which isadministered is 3-(4-piperidinopheny1) propylamine or a pharmaceuticallyacceptable acid addition salt thereof.

7. A method as defined in Claim 2, wherein the compound which isadministered is 2-(3-chloro-4-piperidinophenyl)propylamine or apharmaceutically acceptable acid addition salt thereof.

8. A method as defined in Claim 2, wherein the compound which isadministered is 3-chloro-4-piperidino- 16 phenylethylamine or apharmaceutically acceptable acid addition salt thereof.

9. A method as defined in Claim 1, wherein the compound which isadministered is 4-(4-piperidin0phenyl) butylamine or a pharmaceuticallyacceptable acid addition salt thereof.

10. A method as defined in Claim 1, wherein the compound which isadministered is 4-(3-chloro-4-pipen'dinophenyl)butylamine or apharmaceutically acceptable acid addition salt thereof.

References Cited FOREIGN PATENTS 705,506 3/1954 Great Britain 260-5703STANLEY I. FRIEDMAN, Primary Examiner UNITED STATES PATENT AND TRADEMARKOFFICE CERTIFICATE OF CORRECTION PATENT NO.' 1 3,83 ,9 3 DATED August20, 1974 |NV ENTOR(S) William Robert Nigel Williamson, et al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 2, line 55, change "-CH to --(CH Column 5, line 19, in the secondformula, the R" in the upper-right hand corner should be "R Column 5,line 6, change "examples" to --example.

Column 5, line 56, change "hydroxyamino-O-sulphonic" to-hydroxylamine-O-sulphonic--.

Column 6, line 62, change "B-campho-" to --f -camphor--.

Column 7, line 37, change "quater" to --quarter-- Column 7, line 39,change formulation" to --formulations--.

Column 8, line 10, after "2-(3-" insertchloro-4piperidophenyl)-propylamine dihydrochloride-.

Column 11, line 12, after "(H-Piperidinophenyl", insert Column 12, line16, y should be --isocyanate--.

Signed and Scaled this Twenty-ninth .Day of March 1977 [SEAL] A ttes t:

RUTH C. MASON C. MARSHALL DANN Arresting Offife Commissioner uj'Paremsand Trademarks

